A multicenter, open-label, single-arm phase 1/2 study to evaluate the safety and efficacy of FCN-159 in pediatric participants with neurofibromatosis type 1.
Authors: Xiaojie Hu, JinHu Wang, Wenbin Li, Kang Zeng, Yanling Li, Juan Tao, Zhonghai Guan, Zhuang Kang, Zhongyuan Xu, Changxing Li, Yaohui Ma, Liu Yang, Zhuli Wu, Pu Han, Hongmei Lin, Ben Li, Ai-Min Hui, Xingli Wang, Xiaoxi Lin
Journal: Journal of Clinical Oncology (2023)

10023 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by multiple progressive tumor and non-tumor manifestations, with abnormal activating MAPK pathway. Plexiform neurofibromas (PN) presents in 20-50% of NF1 patients (pts) and may cause serious complications. Selumetinib was approved for pediatric pts with NF1-related PN in US and EU, but therapeutic options remain limited in China. FCN-159 is a highly potent selective anti-tumorigenic inhibitor of MEK1/2, potentially effective in NF1-related PN. Methods: This multi-center, open-label phase1/2 clinical trial is the first-in human study to assess safety and efficacy in pediatric pts with NF1-related PN. The primary objective was to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) in the dose escalation, followed by a dose expansion phase 2 to evaluate safety and efficacy. The starting dose in pediatric pts was determined according to the adults in the dose-escalation phase (previously published in ASCO 2022, abstract no. 3011). Here, we first present the safety and efficacy results in pediatric participants. Results: As of data cut-off (November 21, 2022), 65 pts were enrolled, 19 pts in phase 1 and 45 pts in phase 2. A dose of 4 mg/m 2 (10 pts) and 5 mg/m 2 (9 pts) were evaluated in phase 1 and no DLT was observed. Pediatric pts in the 5 mg/m 2 cohort achieved similar exposure to the 8 mg adult cohort. AUC simulation from population PK model at different BSA ranges were also similar to the adults of 8 mg. Therefore, the RP2D was determined to be 5 mg/m 2 .Treatment-emergent adverse events (TEAEs) were reported in 62 pts (95.4%). Common TEAEs (≥ 20%) were mouth ulcer (43.1%), sinus arrhythmia (36.9%), upper respiratory tract infection (35.4%), folliculitis (21.5%), paronychia (21.5%), and increased blood creatine phosphokinase (20%). 5 pts (7.7%) experienced grade ≥3 treatment-related AEs (TRAEs), including 2 pts (2/10, 10%) in the 4 mg/m 2 group and 3 pts (3/55, 5.5%) in the 5 mg/m 2 group. Grade 3 TRAEs were increased aspartate aminotransferase (1.5%), electrocardiogram QT prolongation (1.5%), folliculitis (3.1%), and dermatitis acneiform (1.5%). No grade ≥ 4 TRAEs were observed. 2 pts (3.1%) reported treatment-related serious adverse events (one case of rhabdomyolysis and dermatitis acneiform each). TEAEs led to dose interruption (26.2%), and discontinuation (1.5%). No reported TEAE led to dose reduction or death. Of the 19 pts with at least one tumor assessment data after baseline, 8 (42%) pts had partial response, 11 (57.8%) with stable disease and none with disease progression. The median DOR could not be evaluated. Conclusions: Overall, FCN-159 was well-tolerated and demonstrated promising anti-tumor activity in pediatric participants with NF1-related PN. Long-term efficacy and safety follow-up are ongoing. Clinical trial information: NCT04954001 .